Substituted benzodioxepins

ABSTRACT

Benzodioxepines of the formula (I) and physiologically tolerated salts and solvates thereof, in which R 1 , R 2 , R 3 , R 4 , A, B, a and b have the meanings indicated in claim  1,  are ligands of the 5HT1A receptors and/or the 5HT4 receptors with simultaneously strong serotonin reuptake inhibition. They can be employed for the treatment and prophylaxis of various diseases.

The invention relates to substituted benzodioxepines of the formula I

-   -   in which    -   R¹, independently of one another, is selected from alkyl,        (CH₂)_(m)OD, (CH₂)_(m)CN, (CH₂)_(m)COR⁵ or (CH₂)_(m)CH₂R5, where        m=0 or 1    -   R², R³, independently of one another, is selected from H, alkyl        having 1 to 5 C atoms,    -   R⁴, independently of one another, is selected from alkyl having        1 to 5 C atoms, heteroalkyl having 1 to 5 C atoms, alkoxy having        1 to 5 C atoms, alkoxyalkyl having 2 to 5 C atoms, Hal, CN, COR⁵        or OH,    -   R⁵ stands for OD, NH₂, NHD or ND₂,    -   A stands for C_(n)H_(2n) where n=2, 3, or 4,    -   B stands for C_(p)H_(2p) where p=0, 1, 2, 3 or 4,    -   D, independently of one another, is selected from H, alkyl        having 1 to 5 C atoms, alkoxyalkyl having 2 to 5 C atoms, aryl        or aralkyl,    -   a, b stand for 0, 1 or 2 and    -   Hal stands for F, Cl, Br or I,        and physiologically tolerated salts and solvates thereof.

Substituted benzodioxepines and the use thereof as pharmaceutical activeingredients for the treatment of hypertension are described, forexample, in DE 2847623, BE 613210, BE 613212 and BE 613215.

The invention was based on the object of finding novel compounds havingvaluable properties, in particular those which are suitable for thepreparation of medicaments.

It has now been found that the compounds of the formula I andphysiologically tolerated salts and solvates thereof have particularlyvaluable pharmacological properties. In particular, they exhibitparticular effects on the central nervous system, especially 5HTreuptake-inhibiting and 5HT-1A-agonistic actions and in some cases veryhigh affinity to the 5HT4 receptor subtype. The compounds according tothe invention furthermore exhibit serotonin-agonistic or antagonisticproperties.

Compounds of the formula I have particularly valuable pharmacologicalproperties. The compounds are particularly suitable for the preparationof medicaments for anxiolytics, antidepressants, antipsychotics,neuroleptics and hypertonics. The compounds of the formula I aresuitable for the treatment and/or prophylaxis of various diseases of thecentral nervous system, such as, for example, strokes, cerebralischaemia and for reducing secondary damage caused by ischaemia, trauma,hypoglycaemia, schizophrenia, depression, dementia, dyskinesia,neurodegenerative diseases, such as Parkinson's disease, ALS,Alzheimer's disease, Lewy bodies dementia or Huntington's syndrome,Tourette's syndrome, anxiety, learning and memory impairment andsleeping disorders, inflammation-induced hyper-algesia, cerebraloedemas, under-supply states (hypoxia).

The compounds of the formula I can furthermore be employed for thetreatment and/or prophylaxis of inflammatory intestinal diseases and theassociated disease symptoms, of functional gastrointestinal diseaseswhich are associated with pain and/or increased or reduced peristalsis,in particular irritable bowel syndrome (IBS), or for the treatment ofnon-ulcer-related dyspepsia, obstipation, in particular opiode-inducedobstipation, of arthritis, migraine, psoriasis or other irritative skindiseases, dysmenorrhoea and fibromylagia.

The compounds of the formula I are also suitable for the treatmentand/or prophylaxis of pain states, in particular pain oversensitivityreactions occurring in back complaints, burn injuries, sunburn andrheumatic diseases, and for the treatment of postoperative pain and theileus which frequently occurs after abdominal operations. In addition,the compounds of the formula I preferably have an analgesic,antiinflammatory, antiasthmatic, diuretic, anticonvulsive,neuroprotective and/or antitussuive action and are therefore preferablysuitable for the treatment of inflammation-induced hyperalgesia, for thetreatment of cerebral oedema, in conditions of under-supply (hypoxia),conditions of pain, and for the amelioration of secondary damage ofischaemia

The compounds of the formula I find further applications in thetreatment and/or prophylaxis of diseases of the bladder, in particularof irritable bladder, cytalgia, cystaigia, neuralgia or bladderneurosis. The term irritable bladder stands for a chronic condition ofirritation of the lower urinary tract which occurs, in particular, inwomen. Symptoms are dysuria, imperative desire to urinate, pollakiuria,suprapubic and diffuse pain on sitting. There is frequently a pronounceddiscrepancy between subjective complaints and the objective findings.The most frequent causes are disorders of the psychovegetative orendocrine system. Irritable bladder should be differentiated from otherclinical pictures, such as urinary tract infections and changes in thelower urinary tract, diseases of adjacent pelvic organs or CNS or spinalcord diseases (for example multiple sclerosis).

For ex-vivo detection of serotonin reuptake inhibition, use can be made,for example, of synaptosomal uptake inhibition (Wong et al.,Neuropsycho-pharmacol. 8 (1993), 23-33) and p-chloroamphetamineantagonism (Fuller et al., J. Pharmacol. Exp. Ther. 212 (1980),115-119).

Binding properties of the compounds of the formula I can be determined,for example, by the 5-HT1A (serotonin) binding test (Matzen et al., J.Med. Chem., 43 (2000), 1149-1157, in particular page 1156 with referenceto Eur. J. Pharmacol.: 140 (1987), 143-155).

For determination of the binding properties of the compounds of theformula I to the 5-HT4 receptor, use can be made of the test accordingto Grossman et al. (Grossman et al., Br. J. Pharmacol. 109, (1993),618-24).

The invention relates to the compounds of the formula I and and/orenantiomers, diastereomers, racemates thereof and physiologicallytolerated salts and solvates thereof as ligands of the 5 HT1A receptorsand/or the 5HT4 receptors with simultaneously strong serotonin reuptakeinhibition.

The invention accordingly relates to the compounds of the formula Iand/or enantiomers, diastereomers, racemates thereof and physiologicallytolerated salts and solvates thereof as ligands of the 5HT1A receptorsand/or the 5HT4 receptors with simultaneously strong serotonin reuptakeinhibition for the treatment and/or prophylaxis of various diseases,such as, for example, strokes, cerebral ischaemia and for reducingsecondary damage caused by ischaemia, trauma, hypoglycaemia,schizophrenia, depression, dementia, dyskinesia, neurodegenerativediseases, such as Parkinson's disease, ALS, Alzheimer's disease, Lewybodies dementia or Huntington's syndrome, Tourette's syndrome, anxiety,learning and memory impairment, sleeping disorders, inflammation-inducedhyperalgesia, cerebral oedemas, under-supply states (hypoxia),inflammatory intestinal diseases and the associated disease symptoms,functional gastrointestinal diseases which are associated with painand/or increased or reduced peristalsis, in particular irritable bowelsyndrome, for the treatment and/or prophylaxis of non-ulcer-relateddyspepsia, obstipation, in particular opiode-induced obstipation,arthritis, migraine, psoriasis or other irritative skin diseases,dysmenorrhoea, fibromylagia, pain states, in particular painoversensitivity reactions occurring in back complaints, burn injuries,sunburn and rheumatic diseases, postoperative pain and the ileus whichfrequently occurs after abdominal operations, diseases of the bladder,in particular of irritable bladder, cytalgia, cystalgia, neuralgia orbladder neurosis.

The invention accordingly also relates to the use of the compounds ofthe formula I and/or enantiomers, diastereomers, racemates thereof andphysiologically tolerated salts and solvates thereof for the preparationof a medicament for the treatment and/or prophylaxis of variousdiseases, such as, for example, strokes, cerebral ischaemia and forreducing secondary damage caused by ischaemia, trauma, hypoglycaemia,schizophrenia, depression, dementia, dyskinesia, neurodegenerativediseases, such as Parkinson's disease, ALS, Alzheimer's disease, Lewybodies dementia or Huntington's syndrome, Tourette's syndrome, anxiety,learning and memory impairment, sleeping disorders, inflammation-inducedhyperalgesia, cerebral oedemas, under-supply states (hypoxia),inflammatory intestinal diseases and the associated disease symptoms,functional gastrointestinal diseases which are associated with painand/or increased or reduced peristalsis, in particular irritable bowelsyndrome, for the treatment and/or prophylaxis of non-ulcer-relateddyspepsia, obstipation, in particular opiode-induced obstipation,arthritis, migraine, psoriasis or other irritative skin diseases,dysmenorrhoea, fibromylagia, pain states, in particular painoversensitivity reactions occurring in back complaints, burn injuries,sunburn and rheumatic diseases, postoperative pain and the ileus whichfrequently occurs after abdominal operations, diseases of the bladder,in particular of irritable bladder, cytalgia, cystalgia, neuralgia orbladder neurosis.

The compounds of the formula I and/or enantiomers, diastereomers,race-mates thereof and physiologically tolerated salts and solvatesthereof can be employed as medicament active ingredient in human andveterinary medicine.

The compounds of the formula I and also the starting materials for theirpreparation are, in addition, prepared by methods known per se, asdescribed in the literature (for example in the standard works, such asHouben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use can also be made here of variants known per se which are notmentioned here in greater detail.

The compounds of the formula I can preferably be obtained by reactingcompounds of the formula II with compounds of the formula III,preferably with compounds of the formula IIa or compounds of the formulaIV with compounds of the formula V.

The invention therefore relates to a process for the preparation of thecompounds of the formula I and physiologically tolerated salts andsolvates thereof, characterised in that

a) a compound of the formula II

-   -   -   in which L¹ denotes H or a metal ion and R¹, R², R³, A and a            have the meanings indicated above and below for the            compounds of the formula I,

b) is reacted with a compound of the formula III

-   -   -   preferably with a compound of the formula IIIa        -   where, in the formula III and IIIa, R⁴ and b have the            meanings indicated above and below for the compounds of the            formula I,

c) a reduction step is optionally carried out and

d) the resultant compound of the formula I is optionally converted intoone of its salts by treatment with an acid.

The invention furthermore relates to a process for the preparation ofthe compounds of the formula I and physiologically tolerated salts andsolvates thereof, characterised in that

a) a compound of the formula IV

-   -   -   in which L² denotes Cl, Br, I, OH, a reactively esterified            OH group or a diazonium group and R¹, R², A and a have the            meanings indicated above and below for the compounds of the            formula I,

b) is reacted with a compound of the formula V

-   -   -   in which R3, R⁴, B and b have the meanings indicated above            and below for the compounds of the formula I,        -   and optionally

c) the resultant compound of the formula I is converted into one of itssalts by treatment with an acid.

The processes according to the invention can be carried out in the senseof a one-pot reaction, i.e. isolation and/or purification steps areomitted as far as possible and only the desired end product is purifiedand/or isolated. Alternatively, a purification and/or isolation step canbe carried out after each of the said reaction steps. Mixed forms of theabove-described procedures are also conceivable.

Suitable purification and isolation steps are known to the personskilled in the art, for example from Houben-Weyl, Methoden derorganischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag,Stuttgart.

The starting materials, for example the compounds of the formula II,III, IIIa, IV or V, may, if desired, also be formed in situ so that theyare not isolated from the reaction mixture, but instead immediatelyconverted further into the compound of the formula I.

The reaction both of the compounds of the formula II with the compoundsof the formula III, preferably with the compounds of the formula IIIa,and also the reaction of the compounds of the formula IV with thecompounds of the formula V, is generally carried out in an inertsolvent.

Suitable inert solvents are, for example, hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, water, ormixtures of the said solvents.

The reaction of the compounds of the formula IV with compounds of theformula V is generally carried out in the presence of an acid-bindingagent. Suitable acid-binding agents are all bases which are usual inorganic synthetic chemistry, both inorganic and organic, preferablyorganic bases. Examples of suitable organic bases are triethylamine,diisopropylamine (DIPEA), dimethylaniline, pyridine or quinoline. Theaddition of an inorganic base, such as, for example, an alkali oralkaline earth metal hydroxide, carbonate or bicarbonate, or of anothersalt of a weak acid of the alkali or alkaline earth metals, preferablyof potassium, sodium, calcium or caesium, may also be favourable.

The reaction of the compounds of the formula II with the compounds ofthe formula III or IIIa is generally likewise carried out in one of theabove-mentioned inert solvents. It may likewise be advantageous to carryout a reduction step after the reaction of the compound of the formulaII and III or IIIa. Suitable reduction steps are known to the personskilled in the art. The reduction step can preferably be carried out byreduction using metal hydrides, for example complex metal hydrides.Examples of metal hydrides employed are sodium hydride, calcium hydride,sodium borohydride and lithium aluminium hydride, diisobutylaluminiumhydride or NaAl(OCH₂CH₂OCH₃)₂H₂, as well as diborane, if desired withaddition of catalysts, such as BF₃, AlCl₃ or LiBr. Preference is givento reduction using complex metal hydrides, such as NaBH₄ and LiAlH₄.Particular preference is given to reduction using NaBH₄. Suitablesolvents for this purpose are, in particular, ethers, such as diethylether, di-n-butyl ether, THF, dioxane, diglyme or 1,2-dimethoxyethane,as well as hydrocarbons, such as benzene. For a reduction using NaBH₄,primarily alcohols, such as methanol or ethanol, furthermore water andaqueous alcohols are suitable as solvent.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between about −30° C.and 180° C., normally between −20° C. and 140° C., preferably between−10° C. and 130° C. and in particular between about 0° C. and about 120°C.

A base of the formula I can be converted into the associatedacid-addition salt using an acid, for example by reaction of equivalentamounts of the base and the acid in an inert solvent, such as ethanol,and subsequent evaporation. Suitable acids for this reaction are, inparticular, those which give physiologically acceptable salts. Thus, itis possible to use inorganic acids, for example sulfuric acid, nitricacid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid,phosphoric acids, such as orthophosphoric acid, sulfamic acid,furthermore organic acids, in particular aliphatic, alicyclic,araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic,sulfonic or sulfuric acids, for example formic acid, acetic acid,propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinicacid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaricacid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinicacid, isonicotinic acid, methane- or ethanesulfonic acid,ethanedisulfonic acid, 2-hydroxyethane-sulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, naphthalene- mono- and disulfonic acids,laurylsulfuric acid. Salts with physiologically untolerated acids, forexample picrates, can be used for the isolation and/or purification ofthe compounds of the formula I.

The invention relates, in particular, to the compounds of the formula Iin which at least one of the said radicals has one of the preferredmeanings indicated above or below.

For the purposes of the present invention, alkyl denotes a linear orbranched alkyl radical, preferably an unbranched alkyl radical which has1, 2, 3, 4 or 5 C atoms, preferably 1, 2, or 3 C atoms, and may be mono-or poly by halogen (Hal), for example perfluorinated. If an alkylradical is substituted by halogen, it preferably has, independently ofthe number of carbon atoms of the alkyl radical, 1, 2, 3, 4 or 5 halogenatoms. Thus, for example, a methyl group (alkyl radical having 1 carbonatom) may be mono-, di- or trisubstituted by halogen, and an ethyl group(alkyl radical having 2 carbon atoms) may be mono-, di-, tri-, tetra- orpentasubstituted by halogen.

For alkyl groups having more than 2 carbon atoms, the same preferablyapplies as for ethyl groups. Alkyl particularly preferably stands formethyl, ethyl, trifluoromethyl, pentafluoroethyl or propyl, furthermorepreferably for isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, butalso for n-pentyl, neopentyl or isopentyl.

The term alkoxy encompasses the radicals —O-alkyl, where alkyl has theabove-mentioned meaning. Preference is given to the radicals methoxy,ethoxy and propoxy.

The term “alkoxyalkyl” preferably encompasses straight-chain radicals ofthe formula C_(U)H2U+1—O—(CH₂)_(v−), in which u and v each,independently of one another, denote 1, 2, 3 or 4, where the sum of uand v does not, however, exceed 5. Particularly preferably, u=1 and v=1,2, 3 or 4.

The term “aryl” preferably encompasses an unsubstituted or mono- orpolysubstituted benzene ring, for example an unsubstituted orsubstituted phenyl radical or an unsubstituted or mono- orpolysubstituted system of benzene rings, such as, for example,anthracene, phenanthrene or naphthalene ring systems. Examples ofsuitable substituents include alkyl, alkoxy, oxo, hydroxyl, mercapto,amino, nitro, cyano and halogen radicals.

The term “aralkyl” preferably encompasses an aryl radical as definedabove, connected to an alkyl radical as defined above. Examples ofsuitable aralkyl radicals include, but are not restricted to, benzyl,phenylpropyl, phenylbutyl and the like.

The term “heteroalkyl” preferably encompasses an alkyl radical asdefined above in which one or more carbon atoms have been replaced by atleast one oxygen, nitrogen or sulfur atom, for example an alkyloxygroup, such as, for example, kethoxy or ethoxy, or a methoxymethyl,cyano or 2,3-dioxyethyl group, polyoxyethylene or -propylene radicals orpolythioethylene or propylene radicals.

In the compounds of the formula II, L¹ preferably denotes H or a groupwhich activates the amino function, for example a metal ion. In aparticularly preferred embodiment, L¹ denotes H. Suitable metal ionsare, in particular, alkali metal, alkaline earth metal or aluminiumions. Preferred metal ions are alkali metal ions, in particular Li, Naor K. In the case of polyvalent metal ions, a complex of metal ion andtwo or more compounds of the formula III often forms, where the complexstoichiometrically generally includes as many compounds of the formulaIII as corresponds to the valency of the metal ion.

In the compounds of the formula IV, L² preferably denotes Cl, Br, I, OH,a reactively modified OH group, in particular a reactively esterified OHgroup, such as an alkylsulfonyloxy group having 1-6 C atoms (preferablymethylsulfonyloxy) or arylsulfonyloxy group having 6-10 C atoms(preferably phenyl- or p-tolylsulfonyloxy), or a diazonium group. In aparticularly preferred embodiment, L² denotes Cl.

For the purposes of the present invention, the term solvates encompassesa complex of variable stoichiometry comprising a dissolved compound ofthe formula 1 or a salt thereof and a solvent which is inert withrespect to the biological activity of the compound of the formula I.Examples of suitable solvents include, for example, water, methanol,ethanol or acetic acid.

The present invention preferably relates to compounds of the formula Iin which the radicals R² and R³ stand for H, where R¹, R⁴, R⁵, A, B, D,a, b and Hal have the meanings indicated above and below for thecompounds of the formula I.

Preference is furthermore given to compounds of the formula I in whichthe radicals R² and R³ stand for H and at least one radical R¹ standsfor (CH₂)_(m)CN, where R⁴, R⁵, A, B, D, a, b, m and Hal have themeanings indicated above and below for the compounds of the formula I.Of these compounds, particular preference is given to those compounds inwhich R¹ is in the 5-position of the indole ring and a preferably standsfor 1 and m preferably stands for 0.

Further preferred compounds of the formula I are those in which A standsfor C_(n)H_(2n) where n=4 and B stands for C_(p)H_(2p) where p=1 or 0,where R¹, R² R³, R⁴, R⁵, D, a, b, m and Hal have the meanings indicatedabove and below for the compounds of the formula I.

Particularly preferred compounds of the formula I are those in which R¹stands for (CH₂)_(m)CN in the 5-position of the indole ring and a standsfor 1 and m stands for 0, R² and R³ stand for H, A stands forC_(n)H_(2n) where n=4 and B stands for C_(p)H_(2p) where p=1 or 0,where, R⁴, R⁵, D, and Hal have the meanings indicated above and belowfor the compounds of the formula I.

The radicals mentioned above as preferred are also preferred in thecompounds of the formulae II, III, IIIa, IV and V.

In a very particularly preferred embodiment of the present invention,the compounds of the formula I are selected from the followingsub-formulae Ia to Ie and physiologically tolerated salts and solvatesthereof.

N-(3,4-Dihydro-2H-1,5-benzodioxepin-3-yl)-4-(5-cyano-3-indolyl)butyl-amine

3-{4-[7-Methyl-3,4-dihydro-2H-1,5-benzodioxepin-3-ylamino]butyl}indole-5-carbonitrile

3-{4-(6-Methyl-3,4-dihydro-2H-1,5-benzodioxepin-3-ylamino)butyl}indole-5-carbonitrile

3-[4-(6-Methoxy-3,4-dihydro-2H-1,5-benzodioxepin-3-ylamino)butyl]indole-5-carbonitrile

3-[4-(3,4-Dihydro-2H-1,5-benzodioxepin-3-yl)methylamino)butyl]indole-5-carbonitrile

The compounds of the formula I according to the invention may,independently of the choice of the substituents and radicals describedabove, have one or more chiral centres, in particular one or more chiralcarbon atoms. If a compound of defined composition according to theinvention has one or more chiral centres, this compound of definedcomposition may be in the form of different stereoisomers. The presentinvention relates to all possible such stereoisomers of compoundsaccording to the invention, which may be in the form either ofindividual, stereochemically uniform compounds, or in the form ofmixtures of two or more stereochemically uniform compounds. In the caseof mixtures of two or more stereoisomers, the individual stereoisomersmay be present in different or identical proportions. In the case ofmixtures of two stereoisomers which are present in equal proportions andrepresent optical antipodes, the term racemic mixtures is used. Thepresent invention likewise relates to racemic mixtures of compounds ofthe formula I.

The compounds according to the invention can be used as therapeuticagents, diagnostic agents and/or cosmetics or together with one or moreactive ingredients which are different from the compounds according tothe invention and/or adjuvants in the therapeutic agents, diagnosticagents and or cosmetics. The compounds according to the invention areusually employed in the form of pharmaceutical, diagnostic and/orcosmetic formulations. Such formulations and processes for theirpreparation are known to the person skilled in the art.

Examples of such formulations are suspensions, emulsions, solutions,liposomes, salts, pastes, biodegradable polymers, nanoparticles,tablets, coated tablets, dragees, film tablets, capsules, pills,granules, powders, aerosols, drops or sprays comprising at least onecompound according to the invention.

The compounds or formulations according to the invention which compriseat least one compound according to the invention can be administered tohumans or animals, for example locally or systemically and in particularorally, intravenously, intraperitoneally, subcutaneously, transdermally,nasally, buccally and/or iontophoretically.

The invention furthermore relates to the use of the compounds of theformula I and/or physiologically tolerated salts thereof for thepreparation of pharmaceutical compositions, in particular bynon-chemical methods. They can be brought into a suitable dosage formhere together with at least one solid, liquid and/or semi-liquidexcipient or adjuvant and optionally in combination with one or morefurther active ingredients.

The invention furthermore relates to pharmaceutical compositionscomprising an effective amount of at least one of the compounds of theformula I and/or one of its physiologically tolerated salts.

These compositions can be used as medicaments in human or veterinarymedicine. Suitable excipients are organic or inorganic substances whichare suitable for enteral (for example oral), parenteral, topicaladministration or for administration in the form of an inhalation sprayand do not react with the novel compounds, for example water, vegetableoils, benzyl alcohols, alkylene glycols, polyethylene glycols, glyceroltriacetate, gelatine, carbohydrates, such as lactose or starch,magnesium stearate, talc, Vaseline. Suitable for oral administrationare, in particular, tablets, pills, dragees, capsules, powders,granules, syrups, juices or drops, suitable for rectal administrationare suppositories, suitable for parenteral administration are solutions,preferably oily or aqueous solutions, furthermore suspensions, emulsionsor implants, suitable for topical application are ointments, creams orpowders. The novel compounds may also be lyophilised and the resultantlyophilisates used, for example, for the preparation of injectionpreparations. The compositions indicated may be sterilised and/orcomprise adjuvants, such as lubricants, preservatives, stabilisersand/or wetting agents, emulsifiers, salts for modifying the osmoticpressure, buffer substances, colorants, flavours and/or a plurality offurther active ingredients, for example one or more vitamins.

For administration as inhalation spray, it is possible to use sprayswhich comprise the active ingredient either dissolved or suspended in apropellent gas or propellent-gas mixture (for example CO₂ orchlorofluoro-carbons). The active ingredient is advantageously used herein micronised form, in which case one or more additional physiologicallytolerated solvents may be present, for example ethanol. Inhalationsolutions can be administered with the aid of conventional inhalers.

The present invention therefore also relates to processes for thepreparation of pharmaceutical compositions which are characterised inthat a compound of the formula I and/or one of its physiologicaltolerated salts and/or one of its solvates is brought into a suitabledosage form together with at least one solid, liquid or semi-liquidexcipient or adjuvant.

The compounds according to the invention can generally be administeredhere analogously to other known compounds having a similar actionprofile, preferably in dosages of between about 0.05 and 500 mg, inparticular between 0.5 and 100 mg, per dosage unit. The daily dose ispreferably between about 0.01 and 2 mg/kg of body weight. However, thespecific dose for each patient depends on a very wide variety offactors, for example on the efficacy of the specific compound employed,on the age, body weight, general state of health, sex, on the diet, onthe time and method of administration, on the excretion rate, medicamentcombination and severity of the particular disease to which the therapyapplies.

The efficacy of the compounds according to the invention for thetreatment of diseases of the bladder, in particular of irritablebladder, can be determined using conventional methods known from theprior art, for example using the animal models described below, oranalogously thereto.

A model for measuring the effect on urine excretion is described inLipschitz et al., J. Pharmacol. Exp. Ther. 1943; 79: 97-110. Thesubstance to be investigated is administered to rats which hadpreviously been denied food overnight while being given free access towater. Increased urine excretion is provoked by simultaneousintraperitoneal injection of 100 ml/kg of physiological saline solution.Immediately after administration of the substance, the bladder wasemptied by gentle massage of the abdomen above the bladder. The rats aresubsequently kept in metabolism cages in which the urine is collectedover a period of 6 hours. The compounds according to the inventionpreferably increase urine excretion as a function of dose, with, forexample, it being possible to observe the excretion of a greatlyincreased amount of urine, preferably at least a 2-fold greater amountof urine, at a dose of about 100 mg/kg. The effect on urine excretion innormal rats is tested analogously (i.e. without induction of increasedurine excretion, see above). Here too, the compounds according to theinvention preferably increase urine excretion as a function of dose,with it being possible in many cases here to observe the excretion of anincreased amount of urine, for example a 5-fold greater amount of urine,even at lower doses of the compounds according to the invention, forexample at about 30 mg/kg po.

The classical animal model for irritable bladder is described in Ghoniemet al., Neurourol. Urodyn. 1995; 14: 657-65. In female apes, irritablebladder is induced by direct infusion of acetone into the bladder. Theanimals are kept in metabolism cages designed for continuous monitoringof miction (urination) of the animals. The frequency, emptying volumesand flow rate of the urine are measured continuously via urine flowmeters. Comparison of urea absorption before and after acetone infusionshows that urea absorption is drastically increased after acetoneinfusion and only reaches the pre-acetone infusion base value againafter four weeks. Furthermore, considerable changes in bladderphysiology are observed in the first week after acetone infusion: thebladder performance, measured in ml/cm, drops by almost 35%. Theemptying behaviour also changes considerably, with the frequency ofemptying increasing greatly with the picture of frequent dribbling andat the same time with an emptying volume reduced by about 70%.Systematic observation of the behaviour of the animals over four weeksshows reduced frequency of general and in particular social activitiesas behaviour repertoire, while stereotypical, self-directed behaviourpatterns, such as self-grooming, scratching and fondling, increaseconsiderably. These changes in behaviour observed in apes are consistentwith the clinical picture of considerable discomfort and pain. Onadministration the compounds according to the invention in usual dosagesand in particular dosages as described above, such as, for example,dosages of 3, 10, and 30 mg/kg, a dose-dependent normalisation ofbladder function can preferably be observed.

EXAMPLE 1 Synthesis ofN-(3,4-dihydro-2H-1,5-benzodioxepin-3-yl)-4-(5-cyano-3-indole)butylamine(=EMD 76066)

The synthesis of the starting material used here is known from theliterature (Sci. Pharm. 201, 69(1), 11-20).

4 g (24 mmol) of benzo[b]-1,4-dioxepin-3-one and 5.2 g (24 mmol) of3-(4-aminobutyl)-1H-5-indolecarbonitrile are dissolved in 270 ml ofmethanol and refluxed for 2 h. After the batch has been cooled to 10°C., 1.4 g (36 mmol) of sodium borohydride are added in portions, and,after one hour, the mixture is refluxed for one hour. The batch isevaporated to dryness and taken up in ethyl acetate.

After washing with water and drying using magnesium sulfate, the residueis chromatographed over a silica-gel column using a 7:3 mixture of ethylacetate and isopropanol, giving 1.86 g (16%) ofN-(3,4-dihydro-2H-1,5-benzodioxepin-3-yl)-4-(5-cyano-3-indole)butylamine.

m.p.: 166-168° C.

CHN calculated: C, 65.39; H, 5.70; N, 8.80.

CHN found: C, 65.39; H, 5.82; N, 8.77.

[M+H]⁺, (ESI-MS): 362

EXAMPLE 2 Synthesis of3-[4-(3,4-dihydro-2H-1,5-benzodioxepin-3-yl)methylamino)-butyl]indole-5-carbonitrile(=EMD 87322)

The synthesis of the starting material used here is known from theliterature (J. Med. Chem. 1984, 27, 570).

-   -   a) At room temperature, 22.5 ml (81 mmol) of RedAl® are added        slowly to a suspension of 5.2 g (27 mmol) of        3,4-dihydro-2H-1,5-benzodioxepin-2-yl)methylamide, which results        in a temperature increase to 30° C. The resultant solution is        left to cool to room temperature over 2 h. 100 ml of water are        subsequently added dropwise, and the mixture is extracted three        times with 30 ml of ethyl acetate. The combined organic phases        are dried using sodium sulfate and evaporated after the salt has        been filtered off. The resultant oil (4.3 g; 83%) is so clean        that it can be reacted further without further purification.    -   b) 4.3 g (24 mmol) of        4-(3,4-dihydro-2H-1,5-benzobenzodioxepin-3-yl)-methylamine are        dissolved in 100 ml of acetonitrile, and the solution is        refluxed for one hour. After cooling, a solution of 5 g of        3-(4-chloro-butyl)indole-5-carbonitrile is added, and the        mixture is refluxed for a further 18 h (TLC monitoring). After        cooling of the reaction solution, the latter is evaporated to        dryness, stirred with 250 ml of water and extracted three times        with 50 ml of diethyl ether. After the organic phase has been        dried over sodium sulfate, the solvent is removed in a rotary        evaporator, and the resultant 9.2 g of crude substance are        purified over a silica-gel column. The product fraction was,        after evaporation, precipitated from ethyl acetate and pentane,        and the resultant crystals were subsequently recrystallised from        diisopropyl ether and ethyl acetate, giving 0.3 g (4%) of the        product as monohydrate.

m.p.: 78° C.

[M+H]⁺, (ESI-MS): 376

An analogous procedure to Examples 1 and 2 gives the compounds:

3-{4-[7-methyl-3,4-dihydro-2H-1,5-benzodioxepin-3-ylamino]butyl}indole-5-carbonitrile(EMD 85350): [M+H]⁺, (ESI-MS): 376

3-{4-(6-methyl-3,4-dihydro-2H-1,5-benzodioxepin-3-ylamino)butyl}indole-5-carbonitrile(EMD 87319); [M+H]⁺, (ESI-MS): 376

3-[4-(6-methoxy-3,4-dihydro-2H-1,5-benzodioxepin-3-ylamino)butyl]indole-5-carbonitrile(EMD 87326); [M+H]⁺, (ESI-MS): 392

EXAMPLE 3

The efficacy of the compounds of the formula I is checked by means ofthe following investigations:

The serotonin reuptake inhibition was investigated with the aid ofsynaptosomal uptake inhibition by the method of Wong et al.(Neuropsycho-pharmacol. 8 (1993), 23-33).

The binding properties to the 5HT1A receptor was determined with the aidof the 5-HT1A (serotonin) binding test (Matzen et al., J. Med. Chem., 43(2000), 1149-1157, in particular page 1156 with reference to Eur. J.Pharmacol.: 140 (1987), 143-155).

In order to determine the binding properties to the 5-HT4 receptor, usewas made of the test in accordance with Grossman et al. (Grossman etal., Br. J. Pharmacol. 109, (1993), 618-24).

The following values were found here: 5HT1A 5HT4 SSRI Compound (IC₅₀ innmol/l) (IC₅₀ in nmol/l) (IC₅₀ in nmol/l) EMD 76066 0.5 n.p. 8.0 EMD87322 4.0 8.4 0.6 EMD 85350 3.0 n.p. 4.0 EMD 87319 2.0 n.p. 3.0 EMD87326 0.6 n.p. 1.0n.p. = not performed

The examples below relate to pharmaceutical compositions:

EXAMPLE A Injection Vials

A solution of 100 g of the active ingredient of the formula I and 5 g ofdisodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH6.5 using 2N hydrochloric acid, sterile filtered, transferred intoinjection vials, lyophilised under sterile conditions and sealed understerile conditions. Each injection vial contains 5 mg of activeingredient.

EXAMPLE B Suppositories

A mixture of 20 g of the active ingredient of the formula I is meltedwith 100 g of soya lecithin and 1400 g of cocoa butter, poured intomoulds and allowed to cool. Each suppository contains 20 mg of activeingredient.

EXAMPLE C Solution

A solution is prepared from 1 g of the active ingredient of the formulaI, 9.38 g of NaH₂PO₄.2 H₂O, 28.48 g of Na₂HPO₄.12 H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

EXAMPLE D Ointment

500 mg of the active ingredient of the formula I are mixed with 99.5 gof Vaseline under aseptic conditions.

EXAMPLE E Tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is pressed to give tablets in a conventional manner in such away that each tablet contains 10 mg of active ingredient.

EXAMPLE F Coated Tablets

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

EXAMPLE G Capsules

2 kg of active ingredient of the formula I are introduced into hardgelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active ingredient.

EXAMPLE H Ampoules

A solution of 1 kg of active ingredient of the formula I in 60 l ofbidistilled water is sterile filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

1. Benzodioxepines of the formula I

in which R¹, independently of one another, is selected from alkyl,(CH₂)_(m)OD, (CH₂)_(m)CN, (CH₂)_(m)COR⁵ or (CH₂)_(m)CH₂R5, where m=0 or1, R², R³, independently of one another, is selected from H, alkylhaving 1 to 5 C atoms, R⁴, independently of one another, is selectedfrom alkyl having 1 to 5 C atoms, heteroalkyl having 1 to 5 C atoms,alkoxy having 1 to 5 C atoms, alkoxyalkyl having 2 to 5 C atoms, Hal,CN, COR⁵ or OH, R⁵ stands for OD, NH₂, NHD or ND₂, A stands forC_(n)H_(2n) where n=2, 3, or 4, B stands for C_(p)H_(2p) where p=0, 1,2, 3 or 4, D, independently of one another, is selected from H, alkylhaving 1 to 5 C atoms, alkoxyalkyl having 2 to 5 C atoms, aryl oraralkyl a, b stand for 0, 1 or 2 and Hal stands for F, Cl, Br or I andphysiologically tolerated salts and solvates thereof.
 2. Benzodioxepinesof the formula I according to claim 1, characterised in that theradicals R² and R³ stand for H.
 3. Benzodioxepines of the formula Iaccording to claim 1, characterised in that the radicals R² and R³ standfor H and at least one radical R¹ stands for (CH₂)_(m)CN. 4.Benzodioxepines of the formula I according to claim 1, characterised inthat a (CH₂)_(m)CN is in the 5-position of the indole ring and apreferably stands for 1 and m preferably stands for
 0. 5.Benzodioxepines of the formula I according to claim 1, characterised inthat A stands for C_(n)H_(2n), where n=4 and B stands for C_(p)H_(2p)where p=1 or
 0. 6. Benzodioxepines of the formula I according to claim1, characterised in that R¹ stands for (CH₂)_(m)CN in the 5-position ofthe indole ring and a stands for 1 and m stands for 0, R² and R³ standfor H, A stands for C_(n)H_(2n) where n=4 and B stands for C_(p)H_(2p)where p=1 or
 0. 7. Benzodioxepines of the formula I according to claim 1selected from the group consisting ofN-(3,4-dihydro-2H-1,5-benzodioxepin-3-yl)-4-(5-cyano-3-indolyl)butylamine,3-{4-[7-methyl-3,4-dihydro-2H-1,5-benzodioxepin-3-ylamino]butyl}indole-5-carbonitrile,3-{4-(6-methyl-3,4-dihydro-2H-1,5-benzodioxepin-3-ylamino)butyl}indole-5-carbonitrile,3-[4-(6-methoxy-3,4-dihydro-2H-1,5-benzodioxepin-3-ylamino)butyl]indole-5-carbonitrileand3-[4-(3,4-dihydro-2H-1,5-benzodioxepin-3-yl)methylamino)butyl]indole-5-carbonitrile.8. Process for the preparation of benzodioxepines of the formula Iaccording to claim 1, characterised in that a) a compound of the formulaII

in which L¹ denotes H or a metal ion and R¹, R², R³, A and a have thethe meanings indicated in claim 1, b) is reacted with a compound of theformula III

where, in the formula III, R⁴ and b have the meanings indicated aboveand below for the in claim 1, and optionally c) a reduction step isoptionally carried out and d) the resultant compound of the formula I isoptionally converted into one of its salts by treatment with an acid. 9.Process for the preparation of benzodioxepines of the formula 1according to claim 1 and physiologically tolerated salts and solvatesthereof, characterised in that a) a compound of the formula IV

in which L² denotes Cl, Br, I, OH, a reactively esterified OH group or adiazonium group and R¹, R², A and a have the meanings indicated in claim1, b) is reacted with a compound of the formula V

in which R³, R⁴, B and b have the meanings indicated in claim 1, andoptionally c) the resultant compound of the formula I is converted intoone of its salts by treatment with an acid.
 10. Compounds of the formula1 according to claim 1 and/or physiologically tolerated salts andsolvates thereof as medicaments.
 11. Use of the compounds of the formula1 according to claim 1 for the preparation of a medicament for thetreatment and/or prophylaxis of various diseases, such as, for example,strokes, cerebral ischaemia and for reducing secondary damage caused byischaemia, trauma, hypoglycaemia, schizophrenia, depression, dementia,dyskinesia, neurodegenerative diseases, such as Parkinson's disease,ALS, Alzheimer's disease, Lewy bodies dementia or Huntington's syndrome,Tourette's syndrome, anxiety, learning and memory impairment, sleepingdisorders, inflammation-induced hyperalgesia, cerebral oedemas,under-supply states (hypoxia), inflammatory intestinal diseases and theassociated disease symptoms, functional gastrointestinal diseases whichare associated with pain and/or increased or reduced peristalsis, inparticular irritable bowel syndrome, for the treatment and/orprophylaxis of non-ulcer-related dyspepsia, obstipation, in particularopiode-induced obstipation, arthritis, migraine, psoriasis or otherirritative skin diseases, dysmenorrhoea, fibromylagia, pain states, inparticular pain oversensitivity reactions occurring in back complaints,burn injuries, sunburn and rheumatic diseases, postoperative pain andthe ileus which frequently occurs after abdominal operations, diseasesof the bladder, in particular of irritable bladder, cytalgia, cystalgia,neuralgia or bladder neurosis.
 12. Process for the preparation of apharmaceutical composition, characterised in that at least one compoundof the formula I according to claim 1 and/or one of its physiologicallytolerated salts or solvates is brought into a suitable dosage formtogether with at least one solid, liquid or semi-solid excipient oradjuvant.
 13. Pharmaceutical composition, characterised in that itcomprises an effective content of at least one compound of the formula Iaccording to claim 1 and/or one of its physiologically tolerated saltsor solvates.